There is an acute and urgent need to develop new and effective pharmacological interventions for posttraumatic stress disorder (PTSD), as there are currently only two FDA-approved medications for the treatment of PTSD (both of which are from the same drug class and have shown only moderate effect sizes in FDA registration trials). Many Veterans with PTSD thus remain symptomatic despite the availability of these treatments, increasing the likelihood of receiving pharmacological treatment interventions for which there is little or no empirical evidence. Randomized controlled trials (RCT) utilizing new medication approaches are thus acutely needed in the Iraq/Afghanistan-era Veteran population, a cohort that may be less treatment- refractory (particularly if treated early in the course of PTSD symptom development). The investigation of promising pharmacological agents for this Veteran cohort could thus not be more timely or urgent. Increasing evidence supports a potential role for neurosteroids in the neurobiology and treatment of PTSD. For example, allopregnanolone (a downstream metabolite of pregnenolone) has anxiolytic, antidepressant, anti- aggressive, fear-reductive, neuroprotective, anti-inflammatory, and neurogenesis-enhancing actions ? and these properties could have clear therapeutic utility for PTSD. Our preliminary data also demonstrate that serum allopregnanolone levels are significantly decreased in patients with PTSD compared to control participants in two independent cohorts. We have shown in multiple studies that pregnenolone administration elevates downstream allopregnanolone levels 5-10 fold, and can thus potentially serve as a precursor loading strategy to restore deficient allopregnanolone levels in PTSD. Furthermore, recent neuroimaging studies demonstrate that allopregnanolone plays a role in the modulation of brain function associated with negative emotion, and enhances activity associated with emotional regulatory processes (Sripada, 2013; Priority Communication, Biological Psychiatry). In addition, our preclinical rodent models demonstrate that pre- treatment with pregnenolone mitigates anxiety-like behaviors in rodents following predator stress exposure. Finally, we have demonstrated that PTSD symptoms improve in Veterans with mild Traumatic Brain injury (mTBI) following administration of pregnenolone in both a pilot RCT and in a larger follow-up RCT in mTBI. In both studies, Veterans with mTBI randomized to pregnenolone showed marked elevations in serum allopregnanolone and pregnenolone levels post-treatment. A precursor loading strategy to enhance deficient levels of endogenous allopregnanolone may thus be an efficacious treatment for PTSD. We therefore propose: 1.) To investigate the potential efficacy of pregnenolone to treat PTSD in Iraq/Afghanistan-era Veterans by conducting an RCT of pregnenolone vs. placebo (primary endpoint CAPS-5 change; [90 randomized participants; n=45 per group;] 8-week duration of treatment), 2.) To determine if pregnenolone also improves co-occurring pain and depression symptoms (secondary endpoints Brief Pain Inventory and Hamilton Depression Rating Scale), 3.) To quantify serum neurosteroid levels at baseline and post-treatment to determine if pregnenolone and downstream neurosteroid metabolites such as allopregnanolone (and other biomarker candidates such as inflammatory markers) are predictors of therapeutic response. Results of the proposed RCT could provide the scientific foundation for the potential efficacy of pregnenolone in PTSD and lead to a pivotal Phase III study. Clinical and preclinical data support the possible therapeutic utility of pregnenolone for PTSD symptoms, pain disorders, and depression, and pregnenolone has been very well-tolerated in Veteran cohorts to date. Treatment with pregnenolone could thus represent a promising new intervention in PTSD that is efficacious, inexpensive, and safe in Iraq/Afghanistan-era Veterans.